U.S. patent application number 13/889259 was filed with the patent office on 2014-11-13 for bioresorbable scaffold for neurologic drug delivery.
The applicant listed for this patent is ABBOTT CARDIOVASCULAR SYSTEMS INC.. Invention is credited to Brenna H. Lord, Terry B. MAZER, Stephen D. Pacetti.
Application Number | 20140336750 13/889259 |
Document ID | / |
Family ID | 51033487 |
Filed Date | 2014-11-13 |
United States Patent
Application |
20140336750 |
Kind Code |
A1 |
MAZER; Terry B. ; et
al. |
November 13, 2014 |
BIORESORBABLE SCAFFOLD FOR NEUROLOGIC DRUG DELIVERY
Abstract
Bioresorbable scaffolds and methods of treatment with such
scaffolds for neurologic disorders including Parkinson's disease,
Huntington's disease, Alzheimer's disease, and brain neoplasms are
disclosed. The bioresorbable scaffold includes a bioresorbable body
and an active agent or drug associated with the body for treating
or ameliorating the neurological disorder. The bioresorbable
scaffold is implanted in the neurological vasculature brain or
brain tissue to provide localized delivery of the drug or active
agent. Embodiments of the invention include scaffolds that are
partially bioresorbable or completely bioresorbable.
Inventors: |
MAZER; Terry B.; (New
Albany, OH) ; Pacetti; Stephen D.; (SanJose, CA)
; Lord; Brenna H.; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT CARDIOVASCULAR SYSTEMS INC. |
Santa Clara |
CA |
US |
|
|
Family ID: |
51033487 |
Appl. No.: |
13/889259 |
Filed: |
May 7, 2013 |
Current U.S.
Class: |
623/1.43 ;
623/1.42 |
Current CPC
Class: |
A61L 2300/45 20130101;
A61L 31/06 20130101; A61L 33/0011 20130101; A61L 2300/416 20130101;
A61L 31/148 20130101; A61L 2300/604 20130101; A61L 31/06 20130101;
A61L 31/16 20130101; A61L 33/0047 20130101; A61L 2300/254 20130101;
C08L 67/04 20130101; A61L 31/146 20130101; A61L 2300/256
20130101 |
Class at
Publication: |
623/1.43 ;
623/1.42 |
International
Class: |
A61L 31/14 20060101
A61L031/14; A61L 33/00 20060101 A61L033/00 |
Claims
1. An implantable bioresorbable scaffold for delivering a drug for
treating a neurological disease in the central nerve system,
comprising: a bioresorbable body; and an active agent associated
with the bioresorbable body, wherein when the scaffold is implanted
in a patient, the active agent, upon coming into contact with a
protein that causes the neurological disease, the active agent
renders the protein nonpathogenic.
2. The scaffold of claim 1, wherein the bioresorbable body
completely resorbs upon completion of active agent delivery.
3. The scaffold of claim 1, wherein the active agent is a protease
that renders the protein nonpathogenic by cleaving the protein.
4. The scaffold of claim 1, wherein the protease is a glutamic
proteases found in filamentous fungi, the glutamic proteases
selected from the group consisting of A4 family of aspatic
endopeptidases and Eqolisins.
5. The scaffold of claim 1, wherein the neurological disease is
Huntington's or Parkinson's disease and the protein is
polyglutamine.
6. The scaffold of claim 1, wherein the active agent is a glutamic
protease
7. The scaffold of claim 1, wherein the active agent is a caspace,
calpain inhibitor, or an inhibitor of .beta.-secretase.
8. The scaffold of claim 1, wherein the active agent is immobilized
on the scaffold such that the active agent cannot be released from
the bioabsorbable body without bioresorption of the body.
9. The scaffold of claim 1, wherein the active agent is distributed
throughout the bioresorbable body.
10. The scaffold of claim 1, wherein the active agent is
distributed at a surface of the bioresorbable body.
11. The scaffold of claim 1, wherein at least a portion of the
bioresorbable body comprises a porous network and the active agent
is distributed throughout network.
12. The scaffold of claim 1, further comprising an mTOR inhibitor
that is released to promote clearance of pathogenic protein bodies
by autophagy, the mTOR inhibitor is selected from the group
consisting of everolimus, zotarolimus, temsirolimus, deforolimus,
ridaforolimus, merilimus, biolimus, umirolimus, myolimus, and
novolimus.
13. The scaffold of claim 1, further comprising an anticoagulant or
antithrombotic agent which is released to reduce scaffold
thrombosis.
14. The scaffold of claim 1, wherein the bioresorbable body
comprises releasable particles including the active agent, wherein
the releasable particles are released from the bioresorbable body
after implantation of the scaffold in a patient.
15. The scaffold of claim 14, wherein the particles have an
affinity for vasculature and selectively bind to the vasculature
upon release from the bioresorbable body.
16. A method for treating or ameliorating a neurological disease in
the central nervous system, comprising: implanting a bioresorbable
scaffold in a blood vessel of the central nervous system of a
patient in need of treatment or amelioration a neurological
disease, wherein the bioresorbable scaffold comprises an active
agent; and allowing the active agent from the implanted scaffold to
come into contact with a protein that causes the neurological
disease and to render the protein nonpathogenic.
17. The method of claim 16, wherein the bioresorbable scaffold
completely resorbs upon completion of active agent delivery.
18. The method of claim 16, wherein the active agent is a protease
that renders the protein nonpathogenic by cleaving the protein.
19. The method of claim 16, wherein the active agent is immobilized
such that the drug is not released from the bioabsorbable body.
20. The method of claim 16, wherein the active agent is selected
from the group consisting of an exoprotease; an endoprotease; a
transglutaminase; and a combination thereof.
21. The method of claim 16, wherein the protein is rendered
nonpathogenic upon cleavage by the active agent of one or more
glutamine-glutamine bond in the protein.
22. The method of claim 16, wherein the bioresorbable scaffold is
implanted upstream of a region displaying the disease and the
active agent is released to allow the active agent to come into
contact with the protein.
23. The method of claim 16, wherein the bioresorbable scaffold is
implanted downstream of a region displaying the disease and the
drug is immobilized on or in the scaffold to allow the scaffold to
come into contact with the protein which allows for continuous
rendering of the protein nonpathogenic.
24. An implantable bioresorbable scaffold for delivering an active
agent for treating Alzheimer's disease in the central nerve system,
comprising: a bioresorbable body; an active agent associated with
the bioresorbable body, wherein when the scaffold is implanted in a
patient, the active agent promotes clearance or removal of the
amyloid plaque found in brain tissue of patients with
Alzheimer's.
25. The scaffold of claim 24, wherein the bioresorbable body
completely resorbs upon completion of active agent delivery.
26. The scaffold of claim 24, wherein the active agent is selected
from the group consisting of Bapineuzumab, Solanezumab, and
Gammagard.
27. The scaffold of claim 24, wherein the active agent is a
protease that degrades .beta.-amyloid which is selected from the
group consisting of insulysin, neprilysin, plasmin, uPA/tPA,
endothelin converting enzyme-1, and matrix metalloproteinase-9.
28. A method for treating or ameliorating Alzheimer's disease,
comprising: implanting a bioresorbable scaffold in a blood vessel
of the central nervous system of a patient in need of the treatment
or amelioration of Alzheimer's disease, wherein the bioresorbable
scaffold comprises an active agent; and allowing the active agent
from the implanted scaffold to come into contact with brain tissue
affected with amyloid plaque and to promote clearance or removal of
the amyloid plaque.
29. The method of claim 28, wherein the bioresorbable scaffold
completely resorbs upon completion of active agent delivery
30. The method of claim 28, wherein the active agent is selected
from the group consisting of Bapineuzumab, Solanezumab, and
Gammagard.
31. An implantable bioresorbable scaffold for delivering an active
agent for treating a brain neoplasm, comprising: a bioresorbable
body, an antineoplastic agent associated with the bioresorbable
body, wherein when the scaffold is implanted in a patient, the
antineoplastic agent contacts brain tissue affected with the
neoplasm and kills or slows growth of malignant cells in the
tissue.
32. A method for treating or ameliorating a brain neoplasm,
comprising: implanting a bioresorbable scaffold in a cerebral
artery supplying blood to a brain neoplasm of a patient in need of
the treatment or amelioration thereof, wherein the bioresorbable
scaffold comprises an antineoplastic drug; and allowing the drug
from the implanted scaffold to come into contact with brain tissue
affected with the neoplasm and kills or slows growth of malignant
cells in the tissue.
33. The method of claim 32, wherein the bioresorbable scaffold
completely resorbs upon completion of drug delivery.
34. The method of claim 32, wherein the active agent is selected
from the group consisting of Afinitor (Everolimus), Avastin
(Bevacizumab), CeeNu (Lomustine), Methazolastone (Temozolomide),
and Carmustine.
35. The method of claim 32, wherein the active agent is released
from the scaffold to come into contact with the brain tissue.
36. The method of claim 32, wherein the implantation is a primary
therapy of treating a tumor in the brain tissue as an alternative
to a resection of the tumor.
37. A bioabsorbable or non-bioabsorbable drug eluting stent with
the drug being a protease to render the disease causing protein
non-pathogenic.
38. The stent of claim 36, wherein the protease comprises an
exoprotease to remove terminal glutamine, an endoprotease to cut at
glutamine, or a transglutaminase, to crosslink glutamines making
the protein inactive.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to bioresorbable implants and methods
of using such implants for treatments of neurologic disorders.
[0003] 2. Description of the State of the Art
[0004] This invention relates generally to treatment of neurologic
disorders with endoprostheses that are adapted to be implanted in
the central nervous system. An "endoprosthesis" corresponds to an
artificial device that is placed inside the body.
[0005] Neurologic disorders include Huntington disease,
Parkinsons's disease, Alzheimer's disease, and brain neoplasms such
as tumors, gliomas and meningiomas. Such neurological diseases are
typically not treated with endoprostheses, i.e., implantation of an
endoprosthesis in the neurovasculature. Therapeutic treatment of
many neurologic disorders has been primarily through systemic
administration of active agents or surgery.
[0006] Patients with coronary artery disease are conventionally
treated with percutaneous interventional procedures (angioplasty
and stenting), coronary artery bypass grafting (surgery) and
medications to improve blood flow to the heart muscle. In
particular, stents are generally cylindrically shaped devices that
function to hold open and sometimes expand a segment of a blood
vessel or other anatomical lumen such as urinary tracts and bile
ducts. A "lumen" refers to a cavity of a tubular organ such as a
blood vessel. Stents are often used in the treatment of
atherosclerotic stenosis in blood vessels, where "stenosis" refers
to a narrowing or constriction of a bodily passage or orifice. In
such treatments, stents reinforce body vessels and prevent
restenosis following angioplasty in the vascular system.
"Restenosis" refers to the reoccurrence of stenosis in a blood
vessel or heart valve after it has been treated (as by balloon
angioplasty, stenting, or valvuloplasty) with apparent success.
[0007] Stents are typically composed of a scaffold or scaffolding
that includes a pattern or network of interconnecting structural
elements or struts, formed from wires, tubes, or sheets of material
rolled into a cylindrical shape. This scaffold gets its name
because it physically holds open and, if desired, expands the wall
of a passageway in a patient. Typically, stents are capable of
being compressed or crimped onto a catheter to a reduced diameter
so that they can be delivered to and deployed at a treatment
site.
[0008] Delivery includes inserting the stent through small lumens
using a catheter and advancing it to the treatment site. Deployment
includes expanding the stent to a larger diameter once it is at the
desired location. Mechanical intervention with stents has reduced
the rate of restenosis as compared to balloon angioplasty.
[0009] Stents are also used as vehicles for providing biological
therapy or drug delivery. Biological therapy uses medicated stents
to locally administer a therapeutic substance. Effective
concentrations at the treated site require systemic drug
administration which often produces adverse or even toxic side
effects. Local delivery is a preferred treatment method because it
administers smaller doses of medication than systemic methods, but
concentrates the drug at a specific site.
[0010] A medicated endoprosthesis may be fabricated by coating the
surface of either a metallic stent or a polymeric scaffold with a
polymeric carrier that includes an active or bioactive agent or
drug. Polymeric scaffolding itself may also serve as a carrier of
an active agent or drug.
[0011] In coronary applications in which the stent maintains
patency of a vessel the stent must be capable of withstanding the
structural loads, namely radial compressive forces, imposed on the
stent as it supports the walls of a vessel. Therefore, a stent must
possess adequate radial strength. Radial strength, which is the
ability of a stent to resist radial compressive forces, relates to
a stent's radial yield strength and radial stiffness around a
circumferential direction of the stent. A stent's "radial yield
strength" or "radial strength" (for purposes of this application)
may be understood as the compressive loading, which if exceeded,
creates a yield stress condition resulting in the stent diameter
not returning to its unloaded diameter, i.e., there is
irrecoverable deformation of the stent. When the radial yield
strength is exceeded the stent is expected to yield more severely
and only a minimal force is required to cause major deformation.
Radial strength is measured either by applying a compressive load
to a stent between flat plates or by applying an inwardly-directed
radial load to the stent.
[0012] Some treatments with stents require its presence for only a
limited period of time. Once treatment is complete, which may
include structural tissue support and/or drug delivery, it may be
desirable for the stent to be removed or disappear from the
treatment location. One way of having a stent disappear may be by
fabricating a stent in whole or in part from a material that
erodes, resorbs or disintegrates through exposure to conditions
within the body. Stents fabricated from biodegradable,
bioabsorbable, bioresorbable, and/or bioerodible materials such as
bioabsorbable polymers can be designed to completely resorb only
after the clinical need for them has ended.
SUMMARY OF THE INVENTION
[0013] Embodiments of the present invention include an implantable
bioresorbable scaffold for delivering a drug for treating a
neurological disease in the central nerve system, comprising: a
bioresorbable body; and an active agent associated with the
bioresorbable body, wherein when the scaffold is implanted in a
patient, the active agent, upon coming into contact with a protein
that causes the neurological disease, the active agent renders the
protein nonpathogenic.
[0014] Embodiments of the present invention include a method for
treating or ameliorating a neurological disease in the central
nervous system, comprising: implanting a bioresorbable scaffold in
a blood vessel of the central nervous system of a patient in need
of treatment or amelioration a neurological disease, wherein the
bioresorbable scaffold comprises an active agent; and allowing the
active agent from the implanted scaffold to come into contact with
a protein that causes the neurological disease and to render the
protein nonpathogenic.
[0015] Embodiment of the present invention include an implantable
bioresorbable scaffold for delivering an active agent for treating
Alzheimer's disease in the central nerve system, comprising: a
bioresorbable body; an active agent associated with the
bioresorbable body, wherein when the scaffold is implanted in a
patient, the active agent promotes clearance or removal of the
amyloid plaque found in brain tissue of patients with
Alzheimer's.
[0016] Embodiments of the present invention include a method for
treating or ameliorating Alzheimer's disease, comprising:
implanting a bioresorbable scaffold in a blood vessel of the
central nervous system of a patient in need of the treatment or
amelioration of Alzheimer's disease, wherein the bioresorbable
scaffold comprises an active agent; and allowing the active agent
from the implanted scaffold to come into contact with brain tissue
affected with amyloid plaque and to promote clearance or removal of
the amyloid plaque.
[0017] Embodiments of the present invention include an implantable
bioresorbable scaffold for delivering an active agent for treating
a brain neoplasm, comprising: a bioresorbable body, an
antineoplastic agent associated with the bioresorbable body,
wherein when the scaffold is implanted in a patient, the
antineoplastic agent contacts brain tissue affected with the
neoplasm and kills or slows growth of malignant cells in the
tissue.
[0018] Embodiments of the present invention include a method for
treating or ameliorating a brain neoplasm, comprising: implanting a
bioresorbable scaffold in a cerebral artery supplying blood to a
brain neoplasm of a patient in need of the treatment or
amelioration thereof, wherein the bioresorbable scaffold comprises
an antineoplastic drug; and allowing the drug from the implanted
scaffold to come into contact with brain tissue affected with the
neoplasm and kills or slows growth of malignant cells in the
tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 depicts an exemplary scaffold.
[0020] FIG. 2 depicts a cross section of scaffold composed of
struts for delivering active agent into the bloodstream.
[0021] FIG. 3 depicts a cross section of a strut of a scaffold for
delivering active agent into tissue of the vessel walls.
DETAILED DESCRIPTION OF THE INVENTION
[0022] All patents, patent publications, and other publications
referred to in this application are incorporated by reference
herein.
[0023] Embodiments of the present invention include a bioresorbable
implant or device, such as a scaffold, and methods of treatment
with such implants for neurologic disorders including Parkinson's
disease, Huntington's disease, Alzheimer's disease, and brain
neoplasms. The bioresorbable implant includes a bioresorbable body,
such as a scaffold structure and an active agent or drug associated
with the body for treating or ameliorating the neurological
disorder. The bioresorbable implant is implanted in the
neurological vasculature of the brain or brain tissue to provide
localized delivery of the drug or active agent. Embodiments of the
invention include implants that are partially bioresorbable or
completely bioresorbable. The bioresorbable body may completely
resorb upon completion of active agent delivery. The complete or
partial resorption of the device allows implantation of another
device, the same or different, at or overlapping the implant site
of the resorbed device.
[0024] The use of a bioresorbable implant for drug delivery to the
brain has several advantages.
[0025] First, a tubular implant such as a scaffold once implanted
is well apposed to the vessel wall and will become embedded in the
vessel wall and reendothelialized. The problems with the
impermeability of the blood-brain barrier are well known. The blood
brain barrier only allows small molecules to enter the brain. The
blood vessels and capillaries of the central nervous system have
endothelium with tight junctions which do not exist in vasculature
outside of the central nervous system. A scaffold implanted in the
arterial system of the brain will bypass the blood-brain
barrier.
[0026] Second, the maximum payload of drug that can be delivered is
higher for a bioresorbable implant than for non-bioresorbable
implant. As much as the entire scaffold in terms of the bulk of the
scaffold can be used as a reservoir for drug delivery. Resorption
of the scaffold will result in release of the entire drug
payload.
[0027] Third, after the drug therapy is completed, the implant will
resorb, removing any biocompatibility issues arising from a
permanent presence.
[0028] Fourth, targeted or local delivery of the drug from the
implant to the brain tissue will reduce systemic exposure to the
drug. Thus, higher doses of drugs or more toxic drugs may thus be
used. Additionally or alternatively, a reduction in systemic side
effects may be realized. Lastly, active agents with short in vivo
lifetimes can be released and still achieve efficacious
concentrations in the target tissue.
[0029] Fifth, if additional drug therapy is required, another
implant may be implanted at or near the same implant site.
[0030] Various embodiments of the structure of an implant may be
used. The implant may have a tubular structure with walls
surrounding an inner lumen. An exemplary tubular implant is a stent
or scaffold structure. A scaffold may include a pattern or network
of interconnecting structural elements or struts. An exemplary
structure of a scaffold is shown in FIG. 1. FIG. 1 depicts a
scaffold 10 which is made up of struts 12 with gaps between the
struts. Scaffold 10 has interconnected cylindrical rings 14
connected by linking struts or links 16. The outer surface of the
struts that faces the tissue is the abluminal surface and the inner
surface of the struts facing the lumen of the vessel is the luminal
surface. Scaffold 10 may be formed from a tube (not shown). The
structural pattern of the device can be of virtually any design.
The embodiments disclosed herein are not limited to scaffolds or to
the scaffold pattern illustrated in FIG. 1. Such a tube can be
formed, for example, by extrusion, dip coating onto a form such as
a mandrel, or injection molding.
[0031] A scaffold such as scaffold 10 may be fabricated from a
polymeric tube or a sheet by rolling and bonding the sheet to form
the tube. The tube may initially have no holes or gaps. The
scaffold pattern can then be formed with laser cutting.
[0032] The embodiments are easily applicable to other patterns and
other devices. The variations in the structure of patterns are
virtually unlimited. Other tubular implant structures include
helical structures or tubular structured formed by braiding
filaments.
[0033] In general, the walls of the implant structure can have
gaps, holes, fenestrations that extend between the inner and outer
surface of a wall so that the tissue of the walls of the vessel is
exposed to the lumen through the gaps or holes. The ratio of the
area of the abluminal surface of the struts to the total vessel
surface area (scaffold abluminal surface and area of gaps) may be
5% to 50%. This is also known as the scaffold/artery ratio.
[0034] A scaffold well-apposed to the vessel wall, with the
scaffold/artery ratio described above facilitates
reendothelialization of the scaffold. To achieve good
reendothelialization, the scaffold should not induce chronic
inflammatory response. Such a response may also jeopardize any
protease, protein or antibody therapy as the attracted monocytes,
macrophages, lymphocytes, eosinophils and neutrophils could degrade
the active agent.
[0035] The diameter of the tubular implants as-fabricated (e.g., as
laser cut) or as-deployed may be 2 to 5 mm, or more narrowly, 2 to
2.2 mm, 2.2 to 2.5 mm, 2.5 to 3 mm, 3 to 3.5 mm, 3.5 to 4 mm or 4
to 5 mm. The wall thickness of the implants may be 25 to 200
microns, or more narrowly, 25 to 50 microns, 50 to 100 microns, 100
to 150 microns, or 150 to 200 microns.
[0036] In other embodiments, a tubular implant can have porous
walls that include a three dimensional network of interconnected
pores. Any of the disclosed structures can have porous walls. The
porous structure can be open or closed cell. The pore size (e.g.,
diameter) of any pores or the average pore size may be 10 to 100
microns, 1-10 microns, 10-100 microns or greater than 100 microns.
A porous polymer tube may be formed, for example, by extrusion with
supercritical carbon dioxide.
[0037] Typically, stents are capable of being compressed or crimped
onto a catheter to a reduced diameter so that they can be delivered
to and deployed at a treatment site. Delivery includes inserting
the stent through small lumens using a catheter and advancing it to
the treatment site. Delivery of a stent or scaffold into the
neurovasculature of the brain can include percutaneous access
through the femoral artery or radial artery.
[0038] Deployment includes expanding the stent to a larger diameter
once it is at the desired location. The delivery diameter of the
tubular implants may be 1.5 to 2.5 mm.
[0039] The tubular implant may be balloon expandable or
self-expandable. In the case of a balloon expandable device, the
geometry of the device can be an open cell structure similar to the
stent patterns disclosed herein or a closed cell structure. In a
balloon expandable device, when the device is crimped from a
fabricated diameter to a crimped or delivery diameter onto a
balloon, structural elements plastically deform. Aside from
incidental recoil outward, the device retains a crimped diameter
without an inward force on the crimped device due to the
plastically deformed structural elements. When the device is
expanded by the balloon, the structural elements plastically deform
again.
[0040] In the case of a self-expandable device, when the device is
crimped from a fabricated diameter to a crimped or delivery
diameter on a balloon, structural elements deform elastically.
Therefore, to retain the device at the crimped diameter, the device
is restrained in some manner with an inward force, for example with
a sheath or a band. The crimped device is expanded to an intended
expansion or deployment diameter by removing the inward restraining
force which allows the device to self-expand to the intended
deployment diameter. The structural elements deform elastically as
the device self-expands.
[0041] An as-fabricated diameter of an implant may be 0.7 to 1
times an intended deployment diameter or any value in between and
including the endpoints. An as fabricated diameter may also be 1 to
1.5 times the intended deployment diameter, or any value in between
and including the endpoints.
[0042] An implant such as a scaffold may be made partially or
completely out of a bioresorbable material or materials. After the
implant has served its function of drug delivery, the implant may
partially or completely disappear from the treatment location by
resorbing. Embodiments can include implants fabricated from
biodegradable, bioabsorbable, bioresorbable, and/or bioerodible
materials such as bioresorbable polymers or bioerodible metals that
can be designed to completely erode only after the clinical need
for them has ended. The device may be configured to completely
erode away within 3 months, 3 to 6 months, 6 to 12 months, 12 to 18
months, 18 months to 2 years, or greater than 2 years.
[0043] Bioresorbable polymers for fabricating implants such as
scaffolds include relatively high strength and high modulus
polymers including, but not limited to, poly(L-lactide) (PLLA),
poly(L-lactide-co-D,L-lactide) (PLDLA) and polyglycolide (PGA) and
copolymers and blends thereof, for example,
poly(L-lactide-co-glycolide) (PLGA). The PLGA can have a mole % of
GA between 5 and 50 mol %, or more narrowly, 5-15 mol %. The PLGA
can have a mole % of (LA:GA) of 85:15 (or a range of 82:18 to
88:12), 50:50 (or a range of 48:52 to 52:48), 95:5 (or a range of
93:7 to 97:3), or commercially available PLGA products identified
being 85:15, 50:50, or 95:5 PLGA. High modulus polymers may have a
Tg greater than body temperature or 37 deg C, or greater than 10 or
greater than 20 deg C above human body temperature or 37 deg C.
[0044] Bioresorbable polymers for fabricating implants such as
scaffolds include relatively low modulus polymers including, but
not limited to, poly(4-hydroxybutyrate) (P4HB), polycaprolactone
(PCL), poly(trimethylene carbonate) (PTMC), poly(butylene
succinate) (PBS), and poly(p-dioxanone) (PDO). The implant material
can include blends of low modulus polymers with high modulus
polymers or other low modulus polymers, copolymers (block, random,
or alternating) of low modulus polymers with high modulus polymers
or other low modulus polymers, or any combination thereof. Such low
modulus polymers may have a Tg less than body temperature or 37 deg
C, less than 25 deg C, or less than 0 deg C.
[0045] In some embodiments, the radial strength of the scaffold can
be relatively low since the primary purpose of the device is drug
delivery and not to maintain patency of a vessel an increased
diameter. The radial strength of the scaffold immediately after
expansion to an intended deployment diameter in a vessel may at
most be the radial pressure required for the device to maintain
contact with the vessel wall to remain lodged in the vessel. The
radial strength in this case may be less than 150 mm Hg, 100 to 150
mm Hg, 150-200 mm Hg, 1 to 10 mm Hg, or less than 100 mm Hg. The
radial strength can be based on a diameter of an as-fabricated
device prior to crimping and expansion or a device after it has
been crimped and expanded to an intended deployment diameter. In
this case, the implant material may have a modulus of elasticity
less than 1.5 GPa, 1 GPa, or 0.5 GPa or 0.5 to 1 GPa at 25 deg C,
37 deg C, or in a range of 25 to 37 deg C.
[0046] In other embodiments, the radial strength of the scaffold
can be high enough to maintain patency of a vessel at an increased
diameter once implanted. In such embodiments, the radial strength
can be greater than 200 mm Hg, 200-300 mm Hg, or higher than 350 mm
Hg. In this case, the implant material may have a modulus of
elasticity greater than 2 GPa, 3 GPa, 5 GPa, 7 GPa, or 9 GPa.
[0047] The drug delivery implant may include a base substrate or
structure such as a scaffold, as described herein. The active
agents may be incorporated or associated with the implant substrate
in various ways.
[0048] An active agent or agents may be distributed within a part
or throughout the implant substrate within the material of the
implant.
[0049] An active agent coating may be disposed over an entire
surface of the implant substrate or over a portion of the surface
of the implant substrate. A coating with a particular agent or
agents may be disposed exclusively over an inside surface, outside
surface, or both. A drug delivery coating thickness may be 1
micron, 2 to 3 microns 3 to 4 microns, 4 to 6 microns, 6 to 10
microns, 10 to 20 microns, or greater than 20 microns. Application
of a coating can be through dip-coating, spray-coating, ink-jet
printing, direct dispense, or roller-coating.
[0050] At least a portion of the implant may be porous and the
active agent may be distributed through the porous network. An
entire scaffold body may be porous, the coating may be porous, or
both.
[0051] An implant may be a tube or formed from a tube (e.g., in the
case of a scaffold) having two layers, an inside layer and outside
layer. The layers can be made of different polymers and be
different thickness. The two layer scaffold can be formed by
coextruding layers of two types of polymers to form a two layer
tube and forming a scaffold from the tube by laser cutting the two
layer tube. One or both of the layers can be porous. One or both of
the layers may include an active agent.
[0052] Active agent incorporated within a polymer can be mixed,
dispersed, or dissolved within the polymer.
[0053] The active agents can be incorporated into a carrier polymer
which can include, but is not limited to, polylactide-based
polymers such as poly(D,L-lactide) and copolymers thereof,
polyglycolide-based polymers such as polyglycolide and copolymers
thereof. Carrier polymers can also include other polyesters such as
polycaprolactone, polyanhydrides such as poly(sebacic anhydride),
polyhydroxyalkanoates such as poly(3-hydroxybutyrate),
polyester-amide, hydrophilic polymers such as polyethylene
glycol/oxide, and polyvinylpyrrolidone. Carrier polymers also
include blends of the disclosed polymers and copolymers of the
disclosed polymers. Additional carrier polymers include hydrogels
made from polyethylene glycol, polyvinypyrolidone, polysaccharide,
dextran, hyaluronic acid, glycosaminoglycans, sugar, or copolymers
thereof with a biodegradable polymer such as PDLLA, PGA, or another
family of the carrier polymer.
[0054] Huntington's disease is a neurodegenerative genetic disorder
that leads to production of a protein defect or pathogenic protein.
A genetic basis for Parkinsons's and Alzheimer's diseases is not
firmly established. These diseases are conjectured to be due to
some combination of genetics, injury, environmental factors and
other causes. However, as with Huntingtons's, hallmarks of
Parkinson's and Alzheimer's are defective and pathogenic proteins
which appear to act as prions. For Parkinson's and Huntington's
diseases, the protein defect is a polyglutamine that is above a
certain length. Specifically, polyglutamine that is 36 or more
glutamine units in length is pathogenic. A polyglutamine that has
35 or less repeat units of glutamine is nonpathogenic. The
pathogenic proteins for Huntington's, Parkinson's, and Alzheimer's
diseases originate in the same point in the brain. The brain
naturally attempts to control these proteins by producing
proteases, such as capsases, that attack these polyglutamines.
However, in the brain, proteases are located in proteosomes which
are not highly effective at clearing these disease produced 36 or
more mer polyglutamines. In the process, the polyglutamines are
only partially broken down and are actually converted into prions
that spread the disease throughout the brain. A prion is an
infectious protein particle in a misfolded form lacking nucleic
acid; thought to be the agent responsible for scrapie and other
degenerative diseases of the nervous system. When a prion enters a
healthy organism, it induces existing, properly folded proteins to
convert into the disease-associated, prion form. The prion acts as
a template to guide the misfolding of more proteins into prion
form. These newly formed prions can then go on to convert more
proteins themselves; this triggers a chain reaction that produces
large amounts of the prion form Embodiments of the invention
include a bioresorbable device including a bioresorbable body and
an active agent associated with the bioresorbable body for treating
a neurologic disease caused by the pathogenic protein. The
bioresorbable body may have the structure of a scaffold. The active
agent, upon coming into contact with a protein that causes the
neurological disease, renders the protein nonpathogenic. A method
of treatment includes implanting the bioresorbable device in a
blood vessel of the central nervous system of a patient in need of
treatment or amelioration of a neurological disease and allowing
the active agent from the implanted device to come into contact
with a protein that causes the neurological disease and renders the
protein nonpathogenic.
[0055] The active agent controls or prevents accumulation of the
protein defect which controls progression of the disorder and
symptoms associated with the disorder. Treatment with the implant
thus may halt or slow progression of the disorder which delays
appearance or worsening of the symptoms and prolongs the lifetime
of the patient.
[0056] The drug or active agent can include a protease. In general,
a protease is any enzyme that conducts proteolysis on a protein.
Proteolysis is the breakdown of proteins into smaller polypeptides
or amino acids. The breakdown generally occurs by the hydrolysis of
the peptide bonds that link amino acids together in the polypeptide
chain forming the protein.
[0057] The proteases can either break specific peptide bonds
(limited proteolysis), depending on the amino acid sequence of a
protein, or break down a complete peptide to amino acids (unlimited
proteolysis). The proteases may also crosslink a pathogenic
protein, making the protein nonpathogenic or inactive.
[0058] A protease associated with the scaffold for treating
Huntington's and Parkinson's disease renders polyglutamine
nonpathogenic. The protease can cleave glutamine-glutamine bonds
upon contact with the polyglutamine. Proteolysis by the protease
controls the accumulation of polyglutamine. The protease may
intervene in the initial events leading to pathogenesis in these
diseases or limit further progression of the diseases. Doses of
protease administrable by, for example, a 12 mm long scaffold range
from as low as 50 .mu.g for protease located in a coating to as
high as 5 mg for protease incorporated into the scaffold
backbone.
[0059] The protease associated with the device prior to
implantation may be in a pro-form or inactive state to prevent the
protease from cleaving itself. The protease in the pro-form is
unable to cleave proteins or other protease. Upon implantation the
protease may be activated or changed to an active form so that it
can cleave pathogenic proteins. The protease may be activated by a
stimulus naturally occurring in the physiological environment of
the patient. For example, the protease may be activated by a
protein in bodily fluids. Alternatively, the protease may be
activated by a local change in conditions arising from the device.
For example, a local decrease in pH triggered by the acidic
degradation products of the bioresorbable material of the device
may trigger activation.
[0060] The protease may be an engineered protease exhibiting
substrate specificity for a polyglutamine stretch or sequence of
amino acids in the polyglutamine. The sequence may correspond to 3
or more amino acids. A study has shown that proteolytic cleavage of
polyglutamine stretches by an exemplary protease could be an
effective modality for the treatment of polyglutamine diseases.
Sellamuthu S, et al. (2011) An Engineered Viral Protease Exhibiting
Substrate Specificity for a Polyglutamine Stretch Prevents
Polyglutamine-Induced Neuronal Cell Death. PLoS ONE 6(7): e22554.
doi:10.1371/journal.pone. 0022554. In this study, Hepatitis A virus
(HAV) 3C protease (3CP) was subjected to engineering using a
yeast-based method known as the Genetic Assay for Site-specific
Proteolysis (GASP). Analysis of the substrate specificity revealed
that 3CP can cleave substrates containing glutamine at positions
P5, P4, P3, P1, P2', or P3', but not substrates containing
glutamine at the P2 or P1' positions. To accommodate glutamine at
P2 and P1', key residues comprising the active sites of the S2 or
S1' pockets were separately randomized and screened.
[0061] Glutamic proteases are also found in filamentous fungi.
These include the A4 family of aspatic endopeptidases and the
Eqolisins. (Sims A H, Dunn-Coleman N S, et al. Glutamic Protease
distribution is limited to filamenous fungi. FEMS Microbio Lett
2004; 239: 95-101.) Fungal species producing glutamic proteases
include Phanerochaete chrysosporium, Aspergillus fumigatus,
Aspergillus nidulans, Aspergillus niger, Magnaporthe grisea,
Neurospora crassa, Fusarium graminearum, and Trichoderma
reesei.
[0062] The proteases digest the long protein chains into short
fragments, splitting the peptide bonds that link amino acid
residues. The proteases can include those that cleave or detach
peptide bonds only in selected portions of a pathogenic protein
such as polyglutamine. Exoproteases or exopeptidases detach the
terminal amino acids from the protein chain. Endoproteases or
endopeptidases cleave only internal peptide bonds of a protein.
[0063] The proteases can include transproteases or transpeptidases
which is an enzyme that catalyzes a transpeptidation reaction which
is the transfer of an amino or peptide group from one molecule to
another. In the course of a proteolysis, the transprotease forms an
acylated enzyme as an intermediate in the process.
[0064] The protease(s) associated with the device can include one
or any combination of an exoprotease; an endoprotease; or
transglutaminase. In particular, a protease associated with the
scaffold may be capable of cleaving terminal or internal
glutamine-glutamine bonds of the polyglutamine.
[0065] The active agent such as the protease that renders the
pathogenic protein nonpathogenic may be associated with the
scaffold in various ways, as described herein. The active agent may
be distributed throughout the bioresorbable body, within a coating
including a carrier polymer on at least a portion of the surface of
the device, within at least one of an abluminal or luminal layer of
a scaffold, or on the surface of the device without a carrier
polymer, or any combination of thereof.
[0066] It is the actions of caspaces and calpains which attempt to
cleave polyglutamine sequences thus creating pathogenic proteins.
An alternative approach is the release of molecules that will
inhibit the action of caspaces and calpains. Such inhibitors can be
small molecules, antibodies, peptides, or proteins.
[0067] Alzheimer's and Parkinson's diseases are associated with the
formation in the brain of amyloid fibrils from .beta.-amyloid and
.alpha.-synuclein proteins. (Lashuel H A, Hartley D, et al. Amyloid
pores from pathogenic mutations. Nature 2002; 418:291.) For local
delivery, there are several strategies involving proteases for the
treatment of Alzheimers disease. The enzyme .beta.-secretase has
been implicated in cleaving the amyloid precursor protein
(.beta.APP). Consequently, release of an inhibitor to
.beta.-secretase is one strategy to inhibit formation of the
.beta.-amyloid plaque found in Alzheimer's. Proteases capable of
degrading .beta.-amyloid include insulysin, neprilysin, plasmin,
uPA/tPA, endothelin converting enzyme-1, and matrix
metalloproteinase-9 (Selkoe D J. Clearing the Brain's Amyloid
Cobwebs. Neuron 2001; 32:177-180.).
[0068] In some embodiments, the active agent may be releasable from
the scaffold. Upon implantation, the active agent may be released
from the device to the blood stream or tissue. Active agent on the
surface may be released directly from the surface. Active agent
distributed within a coating carrier polymer or with the polymer of
the scaffold may be released by diffusion through polymer(s) and
from the surface of the device. In such embodiments, the active
agent is not bound in such a way that diffusion of the active agent
is prevented. The release through diffusion of a polymer provides
controlled release of the active agents. The active agents may be
released over a period of 1 day to 2 weeks, 2 weeks to 6 months, 2
weeks to 1 month, 1 to 2 months, 2 to 5 months, 2 to 6 months, or
greater than 6 months.
[0069] In other embodiments, the active agent is immobilized on or
within the device such that release of the active agent through
diffusion or directly from a surface of the implant is prevented.
The active agents remain on or in scaffold for a period of time
until resorption of device material allows release of the active
agent. Therefore, the release of the immobilized active agents is
controlled by the resorption rate of scaffold material.
[0070] "Immobilized" generally refers to the inability of an agent
molecule to diffuse away from a location in or on a substrate
material, such as a coating or scaffold material. In the context of
an immobilized agent in or on a bioabsorbable polymer, the agent is
incapable of diffusing away from its location in or on the coating
material without the chemical breakdown of the biodegradable
substrate material that is directly or indirectly preventing the
agent from diffusing. Indirect or direct bonding of the immobilized
agent to the substrate prevents the agent from diffusing. Thus, the
immobilized agent can diffuse away from a substrate such as a
coating polymer if the coating material that directly or indirectly
binds it to the coating absorbs away.
[0071] Specifically, for both bulk and surface eroding polymers,
exposure of a carrier polymer of a coating or scaffold polymer to
bodily fluids causes hydrolytic degradation of the polymer which
results in chain scission of the coating polymer. As degradation
proceeds, the molecular weight of the species is reduced to a level
that the degradation products are soluble in the bodily fluids and
diffuse away to be metabolized or excreted.
[0072] The active agents may be immobilized, for example, by
covalent bonds to the bioresorbable polymer of a scaffold or
carrier polymer of a coating. For example, the proteases may be
immobilized by a covalent bond (such as an amide bond) to an ester
grafted to a polymer of the scaffold or coating.
[0073] In further embodiments, the scaffold can include both
releasable and immobilized active agents.
[0074] In further embodiments, the active agent may be associated
with a plurality of releasable particles incorporated within or on
a bioresorbable body or scaffold. After implantation, the particles
can be released from the scaffold. After release, the particles can
be transported downstream from the implant site of the device. The
active agent may be incorporated in or on the particles. The active
agent can be encapsulated by particle material, dispersed within
particle material, at a surface of the particle, or any combination
thereof.
[0075] The particles may be incorporated in or on a bioresorbable
body such as a scaffold in various ways. The particles can be
disposed within depots or holes at the surface of the scaffold,
disposed in a coating on the surface of the scaffold, or embedded
or dispersed throughout the scaffold. In one embodiment, the
release of the particles may be due in whole or in part to erosion
or resorption of coating material, substrate material, or material
which binds the particle to or within the scaffold.
[0076] In some embodiments, the active agent can be releasable from
the particles directly from a surface or through diffusion from the
particle material. The active agent can be released from the
particles prior to and after release of the particles from the
scaffold. The active agents can be immobilized in or on the surface
of the particles. Immobilized active agent may eventually be
released from the particle due to resorption of particle
material.
[0077] When the particles are released, the active agent associated
with the particles may contact pathogenic proteins downstream from
the implant and render them nonpathogenic. The released active
agent may also inhibit endogenous enzymes that lead to the
formation of pathogenic proteins. The particles may be designed to
have or selected to have an affinity to a portion of downstream
vasculature. Such particles may selectively bind to a portion,
e.g., by incorporating a peptide or an antibody fragment with
affinity to receptors found on endothelial cells of the
microvasculature into the surface of the particles. The bound
particles may then provide sustained neutralizing of pathogenic
proteins by releasable active agents, immobilized active agents, or
both.
[0078] The particles may have a characteristic length (e.g.,
diameter) in the range of 10 to 100 nm, 100 to 500 nm, 500 nm to 1
micron, 1 micron to 10 microns. Methods for the manufacture of
particles are well known to those skilled in the art.
[0079] The particle material can be a biostable polymer,
biodegradable polymer, bioabsorbable polymer, bioresorbable
polymer, metallic, or ceramic. Such particles may be coated with an
active agent. Exemplary bioresorbable polymers include the
polyesters disclosed herein. Additional bioresorbable polymers
include surface eroding polymers including polyanhydrides and
polyorthoesters. The particles can also encapsulate one or more
active agents by having an outer shell of polymer, metal, or
ceramic with an inner compartment containing one or more active
agents. Encapsulating the agents with a surface eroding polymer can
delay the release of the active agents for a period of time.
Alternatively, the particle may be formed from a precipitate of
neat drug.
[0080] The active agent may be in an encapsulated state in
nanoparticles, nanocapsules, microparticles, microcapsules,
liposomes, micelles, polyplexes, and polymerosomes.
[0081] To maximize surface area, and interaction of the active
agent with tissue, at least a portion of the scaffold may be porous
with protease immobilized throughout the porous network. The
pathogenic protein diffuses into the pores which is then cleaved
into smaller fragments which diffuse out of the scaffold. The
porous network provides a larger surface area for deactivation of
the pathogenic protein.
[0082] In other embodiments, the device may be made from
hydrophilic copolymers can have components that are bioresorbable,
water soluble, gel forming, or any combination thereof. Such
polymers may include polyethylene oxide (PEO) or polyethylene
glycol (PEG), and polyvinylpyrrolidone (PVP), polyvinyl alcohol
(PVA), hyaluronic acid, dextran, glycosaminoglycans, and gelatin.
The device may be made from copolymers of such hydrophilic polymers
and the bioresorbable polymers disclosed herein. The bioabsorbable
body, the coating, or both may be made from such polymers. Upon
implantation, the hydrophilic polymer containing portion of the
polymer may contain up to 50 wt % of water. The device made from
such polymer may be porous to allow water to facilitate permeation
into the hydrophilic polymer.
[0083] Additionally, a woven scaffold composed of fibers or braided
fibers maximizes the surface area for immobilization of proteases
or proteolytic enzymes. A covered scaffold design is another
embodiment with large surface area. The cover may be a film
covering some or all of the gaps in the wall of the scaffold. The
film may be made of a bioresorbable polymer, such as any of those
disclosed herein. The cover may include releasable or immobilized
active agent on the surface or distributed within and throughout
the cover. The cover may also be porous, as described herein. The
active agent in the pores may be releasable or immobilized in the
pores.
[0084] Parkinson's and Huntington's disease initiates in the same
region of the brain called the substantia nigra, which is part of
the basal ganglia. The blood supply to the basal ganglia comes
primarily from the middle cerebral artery, in particular, the
lenticulostriate branches. These are small branches from the middle
cerebral artery that penetrate the basal ganglia.
[0085] The bioresorbable device may be implanted in the middle
cerebral artery, in particular, the lenticulostriate branches. In
some embodiments, the device may be implanted upstream of the
substantia nigra region or the basal ganglia. In such embodiments,
the proteases may be releasable as described herein so that the
released proteases move downstream to the region to deactivate the
pathogenic proteins. Released substances to inhibit select
endogenous enzymes responsible for plaque formation can be
delivered similarly. The device implanted upstream may further
release particles including proteases. The particles may be
designed to bind to vasculature at the region or lenticulostriate
branches. The particles may release proteases or include
immobilized proteases that remain with the bound particles to
continuously deactivate pathogenic proteins.
[0086] A device including immobilized proteases may be implanted
downstream of the substantia nigra region or the basal ganglia. In
this location, the scaffold allows for the continuous removal of
the pathogenic proteins with proteolytic hydrolysis into small
pieces that are not prions and that proteosomes could then remove
without getting inactivated or clogged. The device may provide
protease(s) that allow for optimum efficiency and continuous
cleaning of the enzyme surface for maximum life.
[0087] In further embodiments, an active agent for treating or
ameliorating Huntington's or Parkinson's disease includes an
antibody to polyglutamine. The antibody may include epitope or
antigenic determinant to flag the polyglutamine for removal by
leucocytes, inflammatory cells, or phagocytic cells.
[0088] With Huntington's disease, the polyglutamines behave like
prions so the disease should be treated before symptoms occur to
keep the disease from spreading throughout the brain. The
bioresorbable scaffold may be implanted in the brain of a patient
prior to disease symptoms, for example, prior to prion production.
In this way, the time before disease symptoms appear could be
lengthened. The device may be implanted early in the life of the
patient, for example, in the second or third decade of life. In
addition to prolonging life, such treatment may significantly
reduce the cost of treatment and timeline.
[0089] Alzheimer's patients develop an amyloid plaque that is
protein based which is different from the pathogenic protein of
Huntington's and Parkinson's. Novel active agents that are being
investigated for Alzheimer's are antibodies that promote clearance
or removal of the amyloid plaque found in brain tissue of patients
with Alzheimer's. These are currently being administered
systemically in clinical trials. The specific compounds are
Bapineuzumab from Johnson & Johnson, Solanezumab from Eli Lily,
and Gammagard from Baxter international Inc. Local delivery would
be a more efficient use of the drug.
[0090] Bexarotene (Targretin) produced a dramatic improvement in
mice with Alzheimer's disease (AD) symptoms. Cramer, P E, et al.
Published Online Feb. 9 2012 Science 23 Mar. 2012: Vol. 335 no.
6075 pp. 1503-1506 DOI: 10.1126/science. 1217697. Bexarotene, which
is an oral retinoid that has been FDA-approved for cancer since
2000, may activate retinoid X receptors on brain cells. This
activation could increase concentrations of apolipoprotein E, a
fat-protein complex that removes excess amyloid in the fluid-filled
space between neurons. Bexarotene may also convert microglia into
their alternative activation state, allowing amyloid beta (A.beta.)
phagocytosis.
[0091] When used in mice, the drug was successful in removing the
buildup of amyloid plaque in the brain as well as reversing
cognitive symptoms and memory deficits. Bexarotene is usually
administered orally for cutaneous lymphoma.
[0092] Further embodiments include a bioresorbable device for
treating or ameliorating Alzheimers including a bioresorbable body
including an active agent that when contacted with brain tissue
affected with amyloid plaque, promotes clearance or removal of the
amyloid plaque. A method for treating or ameliorating Alzheimer's
disease includes implanting the bioresorbable scaffold in a blood
vessel of the central nervous system of a patient in need of the
treatment or amelioration of Alzheimer's disease. The drug is
allowed to contact brain tissue affected with amyloid plaque and to
promote clearance or removal of the amyloid plaque. The active
agent may include Bexarotene, Bapineuzumab, Solanezumab, or
Gammagard. The various embodiments disclosed for associating active
agents with a bioresorbable device apply the above-mentioned active
agents for the treatment of Alzheimer's disease.
[0093] Further embodiments of a bioresorbable device for treating
or ameliorating Alzheimer's include a bioresorbable body and a
protease associated with the body that catabolizes amyloid-.beta.
protein. Doses of protease administrable by, for example, a 12 mm
long scaffold range from as low as 50 ug for protease located in a
coating to as high as 5 mg for protease incorporated into the
scaffold backbone. The protease, upon coming into contact with a
protein that causes the neurological disease, renders the protein
nonpathogenic. A method of treatment includes implanting the
bioresorbable device in a blood vessel of the central nervous
system of a patient in need of treatment or amelioration of
Alzheimer's disease and allowing the protease to come into contact
with amyloid-.beta. protein and rendering the protein nonpathogenic
through catabolism. An exemplary protease is neprilysin. Ex vivo
gene delivery of neprilysin has been shown to reduce amyloid plaque
burden in transgenic mice expressing human .beta.-amyloid precursor
protein (APP). Hemming M L, Patterson M, Reske-Nielsen C, Lin L,
Isacson O, et al. (2007) PLoS Med 4(8): e262.
doi:10.1371/journal.pmed.0040262. The various embodiments disclosed
for associating active agents, particularly proteases, with a
bioresorbable device apply to proteases that catabolize
amyloid-.beta. protein for the treatment of Alzheimer's
disease.
[0094] In further embodiments, an active agent for treating or
ameliorating Alzheimer's disease includes an antibody to amyloid
plaque. The antibody may include epitope or antigenic determinant
to flag the amyloid plaque for removal by leucocytes.
[0095] There are further adjunctive pharmacological therapies that
may be used in addition to delivery of proteases, enzyme
inhibitors, antibodies or small molecules. Rapamycin and other mTOR
inhibitors mitigate the toxicity of polyglutamine via upregulation
of an autophagy pathway (Sarkar S, Ravikumar B, et al. Rapamycin
and mTOR-independent autophagy inducers ameliorate toxicity of
polyglutamine expanded huntingtin and related proteinopathies. Cell
Death and Diff 2009; 16:46-56). Other mTOR inhibiting compounds
that could be used in this role are everolimus, zotarolimus,
temsirolimus, deforolimus, ridaforolimus, merilimus, biolimus,
umirolimus, myolimus, and novolimus. These compounds also are
antiproliferative agents and reduce neointimal proliferation with
the effect of improving patency of the scaffolded vascular segment.
Intravascular stents and scaffolds may also experience a very low
rate of thrombotic occlusion. When this risk is present, it is
treated by systemic dual antiplatelet therapy consisting of aspirin
combined with an antiplatelet drug such as ticlopidine,
clopidogrel, prasulgrel, or ticagreleor. While these may be
indicated for a short duration after implantation of the
neurological drug delivery scaffold, the scaffold itself can also
release antithrombotic agents including heparin, hirudin, and
IIbIIIa inhibitors.
[0096] Conventional treatments for symptomatic brain neoplasms such
as brain tumors, gliomas and meningiomas are surgery, radiation
therapy, and chemotherapy. Most patients with clearly identified
tumors undergo surgery to resect as much of the tumor as possible
unless they are contraindicated for surgery. Active agent
administration in conventional chemotherapy is performed
systemically.
[0097] Chemotherapy is aimed at destruction of malignant cells
using a variety of antineoplastic agents that directly affect
cellular growth and development. The agents can slow the growth of
cancer cells and keep the cancer from spreading to other parts of
the body. When a cancer has been removed by surgery, chemotherapy
may be used to keep the cancer from coming back (adjuvant therapy).
Chemotherapy can also ease the symptoms of cancer.
[0098] The chemicals and drugs used in the treatment of cancer may
be divided into several main groups. (1) Alkylating agents are
capable of damaging the DNA of cancer cells, thereby interfering
with the process of replication; they are cell cycle phase
nonspecific. (2) Antimetabolites interfere with the cancer cell's
metabolism. Some replace essential metabolites without performing
their functions, while others compete with essential components by
mimicking their functions and thereby inhibiting the manufacture of
protein in the cell. (3) Antitumor antibiotics are isolated from
microorganisms and affect the function and/or synthesis of nucleic
acids; they are cell cycle phase nonspecific. (4) Alkaloids are
cell cycle phase specific and exert their effect during the M phase
of cell mitosis and causing metaphase arrest. (5) Hormones and
antihormones create an unfavorable environment for cancer cell
growth.
[0099] Chemotherapy or radiation therapy may then be a follow-up
treatment to kill any remaining tumors cells. Oncology drugs
approved by FDA to treat brain cancer include: Afinitor
(Everolimus), Avastin (Bevacizumab), CeeNu (Lomustine),
Methazolastone (Temozolomide) and Carmustine.
[0100] Methods of treatment with a bioresorbable scaffold with
targeted local delivery of antineoplastic agents may provide the
benefits of conventional systemic therapy. Doses of antineoplastic
agents administrable by, for example, a 12 mm long scaffold range
from as low as 50 .mu.g for protease located in a coating to as
high as 5 mg for protease incorporated into the scaffold backbone.
However, the drug is used more efficiently since the dose is
targeted to a specific region of tissue. Additionally, since the
dose is targeted, a patient may suffer from no side effects or
fewer side effects than systemic delivery.
[0101] Embodiments include a bioresorbable device including a
bioresorbable body and an antineoplastic agent associated with the
bioresorbable body. A method of treatment includes implanting the
bioresorbable device in a cerebral artery supplying blood to a
brain neoplasm of a patient in need of the treatment or
amelioration thereof. When the device is implanted in a patient,
the antineoplastic agent is released and contacts the brain tissue
affected with a neoplasm and kills or slows growth of malignant
cells in the tissue. The various embodiments disclosed for
associating active agents with a bioresorbable scaffold and
delivering active agents apply to the above-mentioned active agents
for the treatment of brain neoplasms.
[0102] The treatment with the bioresorbable delivery device, i.e.,
local treatment, can be performed after resection of the neoplasm,
as a substitute for or in addition to conventional chemotherapy or
systemic administration in general. Alternatively, treatment with
the bioresorbable drug delivery device can be performed as primary
therapy without resection of a neoplasm. Conventional chemotherapy
or systemic administration can be performed in addition to the
treatment with the bioresorbable delivery device.
[0103] When a combined local and system treatment is performed, the
treatments can be performed simultaneously or one can be performed
prior to the other. In a combined treatment, the same active agents
can be used for local and systemic treatment or different active
agents may be used.
[0104] A scaffold may be designed so that drug delivery is directed
into the bloodstream and not into the surrounding, abluminal
tissue. FIG. 2 depicts a cross section of one such a design showing
scaffold 100 composed of struts 102. Struts 102 include a luminal
layer 106 and an albuminal layer 104. Layer 106 is a reservoir of
resorbable polymer combined with active agent. Abluminal layer 104
may be a resorbable polymer that has a low permeability to drug. An
impermeable or low permeability resorbable polymer may be a high
crystallinity polymer (e.g., greater than 20%, 30%, or 40%) such as
PLLA, PDLLA, or simply the same polymer as that used in the drug
reservoir only with no drug in it. For many bioresorbable polymers,
the drug permeability is very low and a high loading of drug is
required to make the polymer permeable. The drug reservoir polymer
could be PCL, PDLLA, or a PLGA. The implanted scaffold supplies
drug to the bloodstream that directly feeds the tumor or affected
region.
[0105] In other embodiments, the scaffold may also be implanted in
an artery that lies directly within the tumor. In this case, the
scaffold would be designed to release drug into the surrounding
tissue rather than into the bloodstream as depicted in FIG. 3. FIG.
3 depicts a cross section of a single strut 112 of a bioresorbable
scaffold designed to deliver drug into the vessel wall. Layer 116
is an abluminal layer composed of a resorbable polymer and drug.
Layer 114 is a luminal layer of drug impermeable resorbable
polymer.
[0106] As discussed herein, such a structure as shown in FIG. 3
might be produced by coextruding a tube of the two layers and then
cutting a scaffold from the tube.
[0107] A concern regarding a vascular scaffold in the cerebral
vasculature is the risk of thrombosis leading to occlusion. This
would create an embolic stroke. In the case of placing a scaffold
in an artery feeding a tumor, or placed upstream of a tumor,
thrombotic occlusion would be a more tolerated event since it would
primarily affect diseased tissue. The radial strength and recoil of
the scaffold may only what is necessary to hold the scaffold in
place. A balloon expandable scaffold could be used for drug
delivery, but a self-expanding scaffold, for example, scaffold
concepts built from braided fibers or other low radial force
designs.
[0108] Radiation treatment may also be used for treatment of brain
tumors. Stereotactic radiosurgery is often used where a beam of
radiation exposes the tumor from multiple orientations. This
reduces the radiation dose to the surrounding tissue and maximizes
the dose for the tumor. Such a spatially selective radiation
therapy may be delivered via a bioresorbable scaffold in the form
of a radioactive source placed on the scaffold. The purpose of the
scaffold becomes enabling delivery of the radioactive source to the
tumor site and holding it in the vasculature. The half-life of the
radioisotope may be selected so that by the time the scaffold is
resorbed, the radioactivity of the source has largely decayed.
[0109] Systemic administration can be accomplished orally or
parenterally including intravascularly, rectally, intranasally,
intrabronchially, or transdermally.
[0110] The "glass transition temperature," Tg, is the temperature
at which the amorphous domains of a polymer change from a brittle
vitreous state to a solid deformable or ductile state at
atmospheric pressure. In other words, the Tg corresponds to the
temperature where the onset of segmental motion in the chains of
the polymer occurs. When an amorphous or semi-crystalline polymer
is exposed to an increasing temperature, the coefficient of
expansion and the heat capacity of the polymer both increase as the
temperature is raised, indicating increased molecular motion. As
the temperature is increased, the heat capacity increases. The
increasing heat capacity corresponds to an increase in heat
dissipation through movement. Tg of a given polymer can be
dependent on the heating rate and can be influenced by the thermal
history of the polymer as well as its degree of crystallinity.
Furthermore, the chemical structure of the polymer heavily
influences the glass transition by affecting chain mobility.
[0111] The Tg can be determined as the approximate midpoint of a
temperature range over which the glass transition takes place.
[ASTM D883-90]. The most frequently used definition of Tg uses the
energy release on heating in differential scanning calorimetry
(DSC). As used herein, the Tg refers to a glass transition
temperature as measured by differential scanning calorimetry (DSC)
at a 10-20.degree. C./min heating rate.
[0112] The Tg of a polymer, unless otherwise specified, can refer
to a polymer that is in a dry state or wet state. The wet state
refers to a polymer exposed to blood, water, saline solution, or
simulated body fluid. The Tg of the polymer in the wet state can
correspond to soaking the polymer until it is saturated.
[0113] "Stress" refers to force per unit area, as in the force
acting through a small area within a plane. Stress can be divided
into components, normal and parallel to the plane, called normal
stress and shear stress, respectively. Tensile stress, for example,
is a normal component of stress applied that leads to expansion
(increase in length). In addition, compressive stress is a normal
component of stress applied to materials resulting in their
compaction (decrease in length). Stress may result in deformation
of a material, which refers to a change in length. "Expansion" or
"compression" may be defined as the increase or decrease in length
of a sample of material when the sample is subjected to stress.
[0114] "Strain" refers to the amount of expansion or compression
that occurs in a material at a given stress or load. Strain may be
expressed as a fraction or percentage of the original length, i.e.,
the change in length divided by the original length. Strain,
therefore, is positive for expansion and negative for
compression.
[0115] "Strength" refers to the maximum stress along an axis which
a material will withstand prior to fracture. The ultimate strength
is calculated from the maximum load applied during the test divided
by the original cross-sectional area.
[0116] "Modulus" may be defined as the ratio of a component of
stress or force per unit area applied to a material divided by the
strain along an axis of applied force that results from the applied
force. The modulus typically is the initial slope of a
stress-strain curve at low strain in the linear region.
[0117] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the appended claims are to encompass within their scope all such
changes and modifications as fall within the true spirit and scope
of this invention.
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